In the field of regenerative medicine, soft tissues reconstruction is generally known and, in particular, breast reconstruction is known.
Breast reconstruction aims to restore a breast to near normal shape, appearance and size, following mastectomy, quadrantectomy or lumpectomy, through several plastic surgeries.
The high incidence of breast cancer is a prominent driver for the breast reconstruction market. Currently, there are over 10 million breast cancer survivors worldwide.
These women typically undergo mastectomies (total breast removal), quadrantectomies or lumpectomies (only the tumor and part of surrounding tissue is removed) as part of their treatment.
The loss of a breast may have a profound impact on women's quality of life and breast reconstruction is routinely offered (to 60% of women underwent mastectomy) to improve outcomes.
The known reconstructive options are so far limited to whole breast saline or silicone non-resorbable implants.
Due to the fact that it is difficult to treat a wide variety of soft tissue deficits resulting from quadrantectomy or lumpectomy procedures in patients, according to the known prior art there are very few reconstructive options for those patients.
Another constraint of the known non-resorbable implants is the perception that cancer might not be detected if the area is covered by such non-resorbable implants, which could hide suspicious lesions or rupture in the implants during screening.
Besides implant-based reconstruction/augmentation, fat auto-transplantation represents the only known viable alternative procedure currently available in the field. According to this procedure, the fat is removed by liposuction from different parts of the patient's body and then injected into the breast.
Transplantation of autologous adipose tissue fraction (“free-fat grafting”) rarely achieves sufficient tissue augmentation because of delayed neovascularization of the grafted adipose tissue, with consequent cell necrosis, and graft volume shrinkage, losing up to 60% of its volume after transplantation. This is due to the fact that fat cells require immediate nutrition from the bloodstream in order to survive.
Attempts aiming to obtain implantable adipose tissue substitutes, through the combination of cells, growth factors and three dimensional polymer matrixes, called “scaffold”, are also known in the art.
However the substitutes so far obtained are dimensionally limited, due to the lack of vascularization and efficient transportation of nutrients and oxygen to inner core of the scaffold.
Regarding to the porous polymeric matrixes used in the art to make scaffold, the most investigated for adipose tissue regeneration are mainly natural origin polymers. Limitations of the employment of natural polymers in the development of medical devices which aim to regenerate adipose tissue are mainly related to their elevated costs, variable quality from batch-to-batch, expensive isolation processes and the possibility to cause immune response, due to endotoxins belonging to their allogenic or xenogenic origin.
Due to the limitations of natural polymers, synthetic polymers are becoming a more valid alternative in comparison to natural polymers, thanks to the low cost and the possibility to tune their physico-chemical properties, in order to match the target application.
Currently, the most common limits against the employment of porous synthetic polymers in adipose tissue regeneration are related to their physico-chemical properties, such as mechanical properties, hydrophilic character, and degradation kinetics, which do not exactly match all the requirements of adipose tissue ingrowth in vivo.
Among synthetic polymeric materials used in implantable medical device, polyurethane-based polymers are known.
According to prior art, the employment of polyurethane forms in implantable medical device for breast surgery, is so far limited to the enhancement of biocompatibility of silicon-based breast prostheses, through surface coating of the latter by thin layers of polyurethane foam. For example, according to WO9006094, a polyurethane coating of a silicon-based prosthesis is uniformly mixed to collagen.
Attempts aimed to employ polyurethane-based porous matrices in tissue engineering and regenerative medicine are also known in the art.
Such a class of synthetic biomaterials are mostly studied and developed for bone tissue regeneration, thanks to their high stiffness and creep resistance, in addition to the possibility to introduce inorganic mineral fillers, similar to those abundantly present in bone tissue, in order to increase their osteoconductivity.
According to US20050013793 and US20130295081, it is possible to obtain biodegradable rigid poly(urethane ester) foams for bone tissue engineering, via copolymerization of biodegradable low-molecular weight hard and soft segments (average molecular weight from 200 to 900 Da) into the polymeric structure, by applying a “pre-polymer” casting strategy.
According to CA2574933 A1, biocompatible and biodegradable segmented polyurethanes of controlled hydrophilic to hydrophobic ratio are obtained due to copolymerisation of biodegradable polyols (average molecular weight from 100 to 20,000 Da), and polyisocyanates (average molecular weight from 18 to 1000 Da), according to a “quasi-pre-polymer” casting strategy.
The cross-linked segmented polyurethane foams, synthesized according to CA2574933 A1, are characterized by compressive elastic moduli comprised between 7 and 72 MPa, resulting in rigid foams and more suitable for bone repair but not for soft tissue regeneration.
Applicant has noticed that cross-linked polyurethane foams disclosed in the above documents do not have the mechanical properties required for soft tissue regeneration; in particular, according to the above prior art documents, is not possible to obtain soft foams, having compressive moduli comprised between 5 to 700 kPa.
With regards to scaffold used in adipose tissue substitutes, the possibility to promote angiogenesis and to enhance cell viability, both in vivo and in vitro, through channelization of porous matrices, is known (“Tamplenizza et al. Mol Imaging. 2015 May 1; 14:11-21”, “Zhang et al. Biomaterials. July 2015; 68-77, Tocchio et al, Biomaterials. March 2015, 45; 124-131” and WO20121645512).
According to prior art, developments of channeled porous scaffolds can take place by several techniques, as for example:    1) sacrificial templating, as disclosed in “Tocchio et al. Biomaterials. March 2015, 45; 124-131” and in WO20121645512 A1;    2) injection molding, as disclosed in “Zhi-xiang, et al. Chinese Journal of Polymer Science. 2014, 32(7); 864-870”;    3) phase separation, as disclosed in US2006069435 A1;    4) Selective Laser Sintering (SLS), as disclosed in “Patri K. Venuvinod, Weiyin Ma. Selective Laser Sintering (SLS). Rapid Prototyping, 2004, pp 245-277”;    5) additive manufacturing techniques, as disclosed in “Melchels F P W, Domingos M A N, Klein T J, Malda J, Bartolo P J and Hutmacher D W. Additive manufacturing of tissues and organs Prog. Polym. Sci. 37 (2012) 1079-1104”; and    6) drilling, as disclosed in US20080261306 A1.
However, the Applicant has found that all these techniques present different limitations when used for the fabrication of channelized porous scaffolds at industrial scale; these limitation are related to scalability, cost, complexity and compatibility with different biomaterials.
In particular, for sacrificial methods 1) the limitations are related to:    i) the necessity to dissolve away the sacrificial templates from the porous scaffolds after solidification (this process takes place mainly by extensive exposure of the porous polymer to several washing cycles, which may alter the overall physico-chemical properties of the polymer, in addition to the high impact of these washing cycles on production coasts);    ii) difficulties to obtain homogeneous pores around the sacrificial templates, especially when the porous scaffold is obtained by foaming;    iii) impossibility to obtain complex three-dimensional sacrificial template networks, when the template networks are produced by injection molding;    iv) difficulties to obtain three-dimensional sacrificial template networks by 3D printing of thermo-plastic polymers, due to the collapse of the filaments during polymer deposition (to this purpose, it would be necessary to assemble several 2D templates, which rendered the process more complicated and less versatile).
With regard to the injection molding 2), despite being the most adopted process for polymers shaping on industrial scale, it is not suitable for the production of complex three-dimensional channels inside soft polymeric foams, due to the inevitable alteration of the porous structure and the formation of this non-porous films in proximities of the mold walls, which are usually called “skin”.
For phase separation methods 3), the limitations are related to the prolonged passages to eliminate solvent/non-solvents, which may alter the scaffolds physico-chemical properties in addition to the lack of versatility of the process.
For Selective Laser Sintering method 4), the main disadvantages consist in:    i) the high power consumption, and consequently the elevated process cost;    ii) necessity to control temperatures within 2° C. for the three stages of the method, i.e. preheating, melting and storing.
As for additive manufacturing techniques 5), the main drawbacks consist in    i) high manufacturing costs    ii) limited choice of materials usable    iii) limited scalability due a general slowness of the production process compared with other techniques.
As for common drilling techniques 6), they cannot be applied to soft and flexible porous polymeric matrixes, since the only use of a mandrel to perforate the porous matrix is not able to create stable channels or cavities, due to deformation and the collapse of the latter, under the effect of the local compression force exerted by the mandrel during perforation.
With regard to the common sacrificial and drilling techniques 6) and, in particular, to prior art document US20080261306 A1, a mandrel-based molding technique is used to create rectilinear channels inside a scaffold, in order to improve perfusion for in vitro applications.
However, this technique cannot be applied to most porous biomaterials, since the cells are grown directly on the mandrel before the formation of the solid gel matrix constituting the scaffold and most porous biomaterial synthetic processes do not allow the presence of cells during the curing phase.
In an alternative example disclosed in the same document, the cells are grown in the channel after the removal of the mandrel to form a parent vessel.
In this case, the formation of a parent vessel needs a channel having a continuous wall, without pores or holes, therefore it would not be possible on a channel highly interconnected with pores in a porous biomaterial.
Applicant has also noticed that the most popular current solutions for breast reconstruction can only fill volume deficit after trauma or tumor resection and are not able to effectively:    i) promote the rapid vascularization in vitro and in vivo,    ii) allow a natural and permanent regeneration of large tissue volume, and    iii) restore both function and volume of adipose tissue.